IL‐6 promotes acute and chronic inflammatory disease in the absence of SOCS3

Abstract

The lack of expression of the Suppressor of Cytokine Signalling-3 (SOCS3) or inactivation of the negative regulatory capacity of SOCS3 has been well documented in rheumatoid arthritis, viral hepatitis and cancer. The specific qualitative and quantitative consequences of SOCS3-deficiency on IL-6-mediated pro- and anti-inflammatory responses remain controversial in vitro and unknown in vivo. Mice with a conditional deletion of SOCS3 in hematopoietic cells develop lethal inflammatory disease during adult life and develop gross histopathological changes during experimental arthritis, typified by elevated IL-6 levels. To clarify the nature of the IL-6 responses in vivo, we generated mice deficient in SOCS3 (SOCS3−/Δvav) or both SOCS3 and IL-6 (IL-6−/−/SOCS3−/Δ vav) and examined responses in models of acute and chronic inflammation. Acute responses to IL-1β were lethal to SOCS3−/Δ vav mice but not IL-6−/−/SOCS3−/Δ vav mice, indicating that IL-6 was required for the lethal inflammation induced by IL-1β. Administration of IL-1β to SOCS3−/Δ vav mice induced systemic apoptosis of lymphocytes in the thymus, spleen and lymph nodes that was dependent on the presence of IL-6. IL-6-deficiency prolonged survival of SOCS3−/Δ vav mice and ameliorated spontaneous inflammatory disease developing during adult life. Infection of SOCS3−/Δ vav mice with LCMV induced a lethal inflammatory response that was dependent on IL-6, despite SOCS3−/Δ vav mice controlling viral replication. We conclude that SOCS3 is required for survival during inflammatory responses and is a critical regulator of IL-6 in vivo.

Fluticasone propionate and Salmeterol combination induces SOCS-3 expression in airway epithelial cells

“…To elucidate the role of TS on airway epithelial inflammatory responses, we have analyzed the effect of TS on SOCS-3, an anti-inflammatory molecule expression in BAEpCs. IL-6 levels were altered during acute and chronic inflammatory process and SOCS-3 is the critical regulator of IL-6 [23]. FP reduced the release of IL-6 and IL-8 by inhibiting IKK-b kinase in airway epithelial cells [39].…”

“…SOCS family of inhibitors is comprised of at least eight members of SH2-domain-containing proteins, which are named suppressors of cytokine signaling 1-7 (SOCS 1-7), and cytokine-inducible SH2 (CIS)-containing proteins [22]. In a recent study using SCOS3 knock-out mice Croker et al have demonstrated that SOCS-3 is an essential negative regulator of IL-6, and in the absence of SOCS-3, IL6 promotes inflammation [23]. However, previously IL-6 was found to induce SOCS3 expression in hepatocytes during acute inflammation [49].…”

Socs3

“…The precise pro- and anti-inflammatory effects of IL-6 in the absence of SOCS3 were investigated by crossing Socs3 −/Δvav mice onto an IL-6 −/− background 81 . In the absence of IL-6, Socs3 −/Δvav mice were protected from the lethal inflammatory disease normally observed in adulthood, indicating an essential pro-inflammatory role for IL-6 in disease progression.…”

Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL-6-activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells

“…For example, SOCS3 binds to JAK-phosphorylated receptors, via the SOCS3 SH (Src homology) domain (SH2), thereby inhibiting JAK/STAT3 signalling, and targeting SH2-bound proteins for proteasomal degradation [13]. Consistent with its role as a negative regulator of inflammatory signalling, SOCS3 expression is increased at sites of acute and chronic inflammation [14], and IL-6 has been reported to promote acute and chronic inflammatory disease in the absence of SOCS3 [15]. Moreover, conditional deletion of the Socs3 gene in haemopoietic and endothelial cells of transgenic mice results in death caused by severe inflammatory lesions in the peritoneal and pleural cavities [16], illustrating its important protective role.…”